Table1_Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy.docx

Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of lipids within hepatocytes, and is commonly associated with obesity, insulin resistance, and hyperlipidemia. Metformin is commonly used to treat type 2 diabetes mellitus and, in recent years, it was found to play a potential role in the amelioration of NAFLD. However, the mechanisms underlying the protective effect of metformin against NAFLD remain largely unknown. Transcription factor EB (TFEB) is a master transcriptional regulator of lysosomal biogenesis and autophagy and, when activated, is effective against disorders of lipid metabolism. However, the role of TFEB in hepatic steatosis is not well understood. In this report, we demonstrate that the activity of TFEB is reduced in the liver of mice fed a high-fat diet. Metformin treatment significantly reverses the activity of TFEB, and the protective effect of metformin against hepatic steatosis and insulin resistance is dependent on TFEB. We show that metformin-induced autophagy is regulated by TFEB, and our findings reveal that TFEB acts as a mediator, linking metformin with autophagy to reverse NAFLD, and highlight that TFEB may be a promising molecular target for the treatment of NAFLD.

非酒精性脂肪肝病（Nonalcoholic fatty liver disease, NAFLD）是指肝细胞内脂质异常蓄积所致的病症，常与肥胖、胰岛素抵抗及高脂血症密切相关。二甲双胍为临床治疗2型糖尿病的常用药物，近年研究发现其在改善NAFLD方面具有潜在作用。然而，二甲双胍对抗NAFLD的保护作用机制仍未完全阐明。转录因子EB（Transcription factor EB, TFEB）是调控溶酶体生物发生与自噬的核心转录因子，其激活后可有效改善脂质代谢紊乱，但TFEB在肝脂肪变性中的作用尚不明确。本研究证实，高脂饮食喂养小鼠的肝脏组织中TFEB活性显著降低；二甲双胍干预可有效逆转TFEB的活性，且其对抗肝脂肪变性与胰岛素抵抗的保护作用依赖于TFEB。本研究进一步发现，二甲双胍诱导的自噬过程受TFEB调控，研究结果揭示TFEB作为关键介质，将二甲双胍与自噬通路相连以逆转NAFLD，并提示TFEB或可成为治疗NAFLD的潜在分子靶点。